In recent years, some progress has been made in the elucidation of cellular events leading to the development of progression of diseases and other medical conditions characterized by abnormal cell growth. For instance, a great amount of research has centered on the identification of genes which are altered or mutated in cancer relative to normal cells. Nonetheless, current cancer treatment modalities are still inadequate in one or more respects. In cancer patients, the prominent immune depression in response to chemotherapy has been widely confirmed. Accordingly, immunotherapy and immunochemotherapy have drawn much attention as adjuvants to existing cancer treatments. Immunotherapy has been reported as not only restoring or potentiating the specific immune responses against cancer, but also improving the general immunological functions of the patient. However, the immunomodulators used in such therapies tend to act in a non-specific manner against cancer cells and also exert direct cytocidal affects against neoplastic cells and behave in a manner more akin to chemotherapeutic agents.
A variety of non-malignant disease states are also characterized by abnormal cell growth. Allograft rejection and autoimmune diseases, for example, involve immune responses characterized by undesirable proliferative bursts of B-lymphocytes or T-lymphocytes. Current treatment modalities for these diseases and medical conditions typically involve immunosuppresive protocols. In the case of allograft rejection, illustrative protocols have featured the administration of drugs such as azathioprine, cyclosporine, and corticosteroids, all of which cause toxic side-effects to non-lymphoid tissues. The development of pan-T-lymphocyte-specific monoclonal antibodies was purported to be an important refinement in therapy on the basis that antibodies targeted only the T-lymphocytes. However, this therapy has proven to be disadvantageous in that it also destroys T-lymphocytes required for normal immune surveillance.
The phenotype common to cancers and the aforementioned non-malignant diseases is abnormal cell growth. The life cycle of a cell is traditionally divided into four phases, G1 (Gap 1), S (DNA synthesis), G2 (Gap 2), and M (mitosis). In the mitosis phase, chromosomes condense and become visible as discrete bodies. The two centrosomes of the cell move apart to opposite sides of the nucleus, and arrays of microtubules grow from the centrosomes to form a mitotic spindle. The centrosomes thus define the anchoring points for the microtubuli which in turn direct the chromosomes to the proper place in the cell. Some of these microtubules become attached to the kinetochores of the chromosomes. The attached chromosomes become aligned on the metaphase plate, anaphase begins and the chromosomes start moving toward the poles and the poles move apart from each other. Cytokinesis then occurs, wherein the cell pinches and ultimately becomes two G1 phase daughter cells. G1 are not synthesizing DNA, but active in other replication-type activities in order to provide the two daughter cells with the appropriate organelles. G1 cells then proceed into the S phase where the chromosomal DNA of the cell replicates to produce double DNA content. At the boundary of the S and the G2 phases, the replication machinery signals that DNA replication is complete. The cell then enters the G2 phase and prepares for mitosis. Thus, cells in the G2 phase have double DNA content. It is critical that cell division proceeds in an orderly manner such that each daughter cell receives a correct and complete set of chromosomes. Most adult, differentiated non-dividing cells are considered to be in a non-cycling state termed G.sub.0.
If the nechanisms that underlie cell division could be disarmed or inactivated, procedures and perhaps even pharmacologic agents could be developed in an attempt to control or inhibit the growth of unwanted, diseased cells in a wide variety of cancers and non-malignant diseases characterized by abnormal cell growth. It goes without saying that such discoveries would be of pioneering proportions in clinical medicine.